TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy

Jun Ding,Maziar Divangahi,Ekaterina Gusev,Gregory J Fonseca,Feng Liang,Basil J Petrof,Orsolya Lapohos,Salyan Bhattarai,Qian Li,Eva Kaufmann

doi:10.1038/s41467-022-28531-1

Jun Ding, Maziar Divangahi + Show 8 more

Open Access

https://doi.org/10.1038/s41467-022-28531-1

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Abstract

Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. We postulate that an evolutionarily ancient protective mechanism against infection, known as trained immunity, drives pathological inflammation in DMD. Here we show that bone marrow-derived macrophages from a murine model of DMD (mdx) exhibit cardinal features of trained immunity, consisting of transcriptional hyperresponsiveness associated with metabolic and epigenetic remodeling. The hyperresponsive phenotype is transmissible by bone marrow transplantation to previously healthy mice and persists for up to 11 weeks post-transplant. Mechanistically, training is induced by muscle extract in vitro. The functional and epigenetic changes in bone marrow-derived macrophages from dystrophic mice are TLR4-dependent. Adoptive transfer experiments further support the TLR4-dependence of trained macrophages homing to damaged muscles from the bone marrow. Collectively, this suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD.

Highlights

Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease
Macrophage phenotype is modulated by exposure to various pathogen-associated molecular patterns (PAMPs) and endogenous molecules released after tissue injury, which can serve as ligands for classical receptors of innate immunity such as members of the TLR family[14]
After acute muscle injury an initial wave of bone marrow-derived M1-like macrophages populates the muscle, which are replaced by macrophages with a M2-like phenotype[33]

Summary

Introduction

Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. Adoptive transfer experiments further support the TLR4dependence of trained macrophages homing to damaged muscles from the bone marrow This suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD. We generated dystrophin-deficient mdx mice (model of DMD) lacking the chemokine receptor CCR2 and demonstrated the importance of bone marrow (monocyte)-derived macrophages (BMDM) in early pathogenesis of the disease[10]. A cardinal feature of trained immunity is that it lacks antigen-specificity and promotes exaggerated cytokine responses to multiple forms of unrelated pathological stimuli[16] This non-specific hyperresponsiveness of the innate immune system has been mechanistically linked to histone modifications[18,19,20], as well as alterations in cellular metabolism[21]. Initially described in the context of infections, there is increasing evidence that trained immunity may play a deleterious role in different non-infectious diseases associated with chronic sterile inflammation[22,23,24,25]

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